Soft gelatin encapsulation of a solution or suspension of a pharmaceutical agent dissolved or suspended in a medium offers many advantages over other dosage forms such as compressed, coated or uncoated solid tablets, hard dried filled capsules, or bulk liquid preparations. Gelatin encapsulation of a solution or suspension permits accurate delivery of a unit dose. Such uniformity is more difficult to achieve via a tabletting process wherein solids must be uniformly mixed and compressed, or via incorporation of the total dose of active ingredient into a bulk liquid carrier which must be measured out prior to each oral administration. Soft gelatin capsules are also more easily transported by patients than bulk liquids, since only the required number of doses need be removed from the package.
Soft gelatin capsules are favored by many people for oral administration of medications, at least in part because of their ease of swallowing. The soft gelatin shell makes the capsule easier to swallow, especially for the elderly, than a tablet or a hard capsule. Furthermore, the contents of a soft gel capsule can be more bioavailable following ingestion due to rapid rupture of the capsule and release of the contents in the digestive tract. See, for example, U.S. Pat. Nos. 4,597,885, 4,708,834, 4,795,642 and 4,935,243 by the inventor herein.
However, soft gel capsules are formed of a gelatin and glycerol, wherein the capsule wall can be permeable to water vapor. The water can diffuse through the capsule wall into contact with a hydrolytically unstable drug contained within the capsule, causing hydrolysis.
Acetylsalicylic acid (ASA), or aspirin, is an example of a hydrolytically unstable drug. ASA is a commonly used analgesic and anti-inflammatory drug now often used in maintenance doses for prophylaxis of heart attacks and stroke, inhibition of blood coagulation, and prevention of thrombus and stenosis.
ASA has been commercially available in other dosage forms, such as coated or uncoated tablets, but instability of ASA to hydrolysis limits preparation of an oral dosage form that is stable for prolonged storage period sto formulations where the ASA is preserved in a substantially anhydrous state with barrier to contact with atmospheric moisture. A phenolic acetate, ASA hydrolyzes to an equimolar mixture of acetic acid and salicylic acid. These hydrolytic products bring about deleterious insolubilization of the soft gelatin capsule though the denaturing activity of the phenolic and acidic components, mainly salicylic acid.
Salts and buffered forms of ASA have been used, but these forms can act more slowly after ingestion than does ASA itself, and are not as effective as aspirin despite the various beneficial claims made.
Accordingly, there is a need for a formulation of ASA suitable for containment within soft gelatin capsules.